Pinhanços Sandra Sofia, Teixeira de Oliveira João, Alves C Henrique, Deus Cláudia M, de Winter Twan J J, Viana Sofia, Reis Flávio, Santos Jorge, Buitinga Mijke, Carlotti Françoise, Ferreira Lino, Gotthardt Martin, Jones John, Fernandes Hugo
CNC - Center for Neuroscience and Cell Biology, University of Coimbra, 3060-197 Coimbra, Portugal.
IIIUC-Institute of Interdisciplinary Research, University of Coimbra, 3004-517 Coimbra, Portugal.
Mol Ther Nucleic Acids. 2025 Mar 25;36(2):102498. doi: 10.1016/j.omtn.2025.102498. eCollection 2025 Jun 10.
The incidence of type 2 diabetes mellitus (T2DM) is tightly linked to obesity. High levels of circulating glucose and saturated free fatty acids (FFAs), known as glucolipotoxicity (GLT), is implicated in β cell dysfunction and/or death. This study aims to identify miRNAs capable of protecting β cells from GLT-induced cell death (GICD). A library of 2,080 human miRNA mimics was transfected in β cells followed by exposure to GLT. We identified 45 miRNAs capable of protecting β cells from GICD and selected miR-642a-3p for further studies. RNA-seq revealed that miR-642a-3p restored the expression of β cell identity genes and modulated pathways associated with cell survival and lipid metabolism. Moreover, we showed that transfection of β cells with miR-642a-3p protected them from GLT-induced changes in insulin secretion. Compared with the control, hypercaloric-fed mice showed a trend toward decreased expression of GLT-protective miRNAs. Notably, we demonstrated that miR-642a-3p expression was downregulated in human islets isolated from T2DM patients compared with non-diabetic controls. Importantly, in obese patients, the expression of GLT-protective miRNAs in plasma-derived extracellular vesicles was increased in non-diabetic patients. Overall, we have identified a potential dual role for miR-642a-3p as both a biomarker and a facilitator of β cell survival and function, offering a novel theranostic tool for the management of diabetes and/or obesity.
2型糖尿病（T2DM）的发病率与肥胖密切相关。高水平的循环葡萄糖和饱和游离脂肪酸（FFA），即所谓的糖脂毒性（GLT），与β细胞功能障碍和/或死亡有关。本研究旨在鉴定能够保护β细胞免受GLT诱导的细胞死亡（GICD）的微小RNA（miRNA）。将一个包含2080种人类miRNA模拟物的文库转染到β细胞中，随后使其暴露于GLT。我们鉴定出45种能够保护β细胞免受GICD影响的miRNA，并选择miR-642a-3p进行进一步研究。RNA测序显示，miR-642a-3p恢复了β细胞特异性基因的表达，并调节了与细胞存活和脂质代谢相关的信号通路。此外，我们发现用miR-642a-3p转染β细胞可保护其免受GLT诱导的胰岛素分泌变化的影响。与对照组相比，高热量喂养的小鼠中GLT保护性miRNA的表达有降低趋势。值得注意的是，我们证明，与非糖尿病对照组相比，从T2DM患者分离的人胰岛中miR-642a-3p的表达下调。重要的是，在肥胖患者中，非糖尿病患者血浆来源的细胞外囊泡中GLT保护性miRNA的表达增加。总体而言，我们确定了miR-642a-3p作为生物标志物以及β细胞存活和功能促进因子的潜在双重作用，为糖尿病和/或肥胖症的管理提供了一种新的诊疗工具。
